Calcium Role in Gap Junction Channel Gating: Direct Electrostatic or Calmodulin-Mediated?

Area of Science:

• Cell Biology
• Biophysics
• Molecular Biology

Background:

• Gap junction channels regulate intercellular communication.
• Chemical gating of these channels involves cytosolic calcium (Ca2+i).
• Connexins/innexins, the gap junction proteins, lack high-affinity calcium-binding sites.

Purpose of the Study:

• To elucidate the mechanism of calcium-mediated gap junction channel gating.
• To evaluate the proposed role of calmodulin (CaM) in this process.
• To address alternative models suggesting direct calcium-connexin interactions.

Main Methods:

• Review of experimental data including CaM blockers, CaM expression inhibition, CaM mutants, co-localization studies, and connexin mutants.
• Analysis of studies investigating direct calcium-connexin interactions using isolated gap junctions.
• Synthesis of findings from four decades of research.

Main Results:

• Extensive evidence supports calmodulin as the primary mediator of Ca2+ gating.
• Studies involving CaM manipulation and binding site analysis consistently implicate Ca2+-CaM.
• Alternative models proposing direct Ca2+-connexin interactions are not supported by experimental data, even at extremely high calcium concentrations.

Conclusions:

• The Ca2+-CaM-cork model accurately describes gap junction channel gating.
• Direct electrostatic interaction between calcium and connexins is unlikely to be the primary gating mechanism.
• Decades of research confirm the crucial role of Ca2+-calmodulin in regulating gap junction channel function.